Inhalation Of Silica Research Articles

Omega-3 fatty acid intake suppresses induction of diverse autoantibody repertoire by crystalline silica in lupus-prone mice

Inhalation of crystalline silica (cSiO2) in the workplace is etiologically linked to lupus and other autoimmune diseases. Exposing lupus-prone NZBWF1 mice to respirable cSiO2 unleashes a vicious cycle of inflammation and cell death in the lung that triggers interferon-regulated gene expression, ectopic lymphoid structure (ELS) development, elevation of local and systemic autoantibodies (AAbs), and glomerulonephritis. However, cSiO2-induced inflammation and onset of autoimmunity can be prevented by inclusion of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) into the diet of these mice. Since cSiO2 both causes cell death and interferes with efferocytosis, secondary necrosis of residual cell corpses might provide a rich and varied autoantigen (AAg) source in the lung. While it is known that the particle induces anti-nuclear and anti-dsDNA AAbs in NZBWF1 mice, the full extent of the cSiO2-induced AAb response relative to specificity and isotype is not yet understood. The purpose of this study was to test the hypotheses that cSiO2 exposure induces a wide spectrum of AAbs in the pulmonary and systemic compartments, and that dietary DHA intervention prevents these changes. Archived tissue fluid samples were obtained from a prior study in which NZBWF1 mice were fed purified isocaloric diets containing no DHA (control) or DHA corresponding calorically to human doses of 2 and 5 g/day. Mice were intranasally instilled with 1 mg cSiO2 or saline vehicle weekly for 4 weeks, then groups euthanized 1, 5, 9, or 13 weeks post-instillation (PI) of the last cSiO2 dose. Bronchoalveolar lavage fluid (BALF) and plasma from each time point were subjected to AAb profiling using a microarray containing 122 AAgs. cSiO2 triggered robust IgG and IgM AAb responses against lupus-associated AAgs, including DNA, histones, ribonucleoprotein, Smith antigen, Ro/SSA, La/SSB, and complement as early as 1 week PI in BALF and 5 weeks PI in plasma, peaking at 9 and 13 weeks PI, respectively. Importantly, cSiO2 also induced AAbs to AAgs associated with rheumatoid arthritis (collagen II, fibrinogen IV, fibrinogen S, fibronectin, and vimentin), Sjögren’s syndrome (α-fodrin), systemic sclerosis (topoisomerase I), vasculitis (MPO and PR3), myositis (Mi-2, TIF1-γ, MDA5), autoimmune hepatitis (LC-1), and celiac disease (TTG). cSiO2 elicited comparable but more modest IgA AAb responses in BALF and plasma. cSiO2-induced AAb production was strongly associated with time dependent inflammatory/autoimmune gene expression, ELS development, and glomerulonephritis. AAb responses were dose-dependently suppressed by DHA supplementation and negatively correlated with the ω-3 index, an erythrocyte biomarker of ω-3 content in tissue phospholipids. Taken together, these findings suggest that cSiO2 exposure elicits a diverse multi-isotype repertoire of AAbs, many of which have been reported in individuals with lupus and other autoimmune diseases. Furthermore, induction of this broad AAb spectrum could be impeded by increasing ω-3 tissue content via dietary DHA supplementation.

Assessing the geochemical and environmental baseline of heavy metals in soils around hydrothermal hematite-barite-galena veins in Baghin area, Kerman, Iran.

To assess the geochemical and environmental baseline as well as the availability of the heavy elements in soils around the hematite-barite-galena veins in the Baghin area, a total of 70 soil samples were collected and analyzed by ICP-OES for 43 heavy metals and metalloids. Compared to the global soil level or crustal abundance, the calcareous soils are 2-26 magnitudes enriched in Ca, Cu, Pb, Zn, Cd, Se, As, Sb and Sr. The ferruginous soils are highly enriched in Fe, Mo, Pb, Zn, Cd, As, Sb, Ba and Sr, almost 2-49 orders higher than the crustal abundance and global soil level. Additionally, the baritic soils are 3-94 times higher than the crustal and global soil values for Ba, Cu, Mo, Pb, Zn, Ni, Co, Cd, Se, As, Sb and Sr. However, the soils developed on the shale layers are moderately enriched in As, Zn, Se, Sb, Ba, Pb and Sr. The high concentrations of heavy metals are possibly related to the presence of minor sulfide minerals in barite-rich soils or adsorption by Fe-oxy-hydroxides formed by oxidation of sulfide minerals. Therefore, the oxidation of minor sulfide minerals in barite veins may be prone to acid mine generation and of environmental concern. The inhalation of silica dusts released by silica-rich barite ores (20% SiO2) during crushing, milling, as well as using in drilling mud may trigger silicosis. Despite the high baseline values of some heavy metals and metalloids, the presence of Fe-oxy-hydroxides and clay minerals in the soils could play significant roles in sequestering the toxic effects of heavy metals contamination in soil, groundwater, plants, wildlife and humans.

Managing Risks and Exposures to Silica in Training and Assessment Activities in Vocational Education and Training

A number of activities in workplaces, such as such as those including cutting, grinding, sanding, drilling, loading or demolishing products that contain silica, can produce respirable particles of crystalline silica dust that are small enough to inhale. Inhalation of crystalline silica can cause silicosis which is incurable. Work practices are critical to prevent the condition from occurring and safe work practices are as relevant to workplaces as they are to training environments. This study considers methods of risk control and training practices such that silicosis is prevented.Training requirements are profiled in a vocational education and training setting and must include: crystalline silica hazards and health risks, including silicosis; effective use controls; use and maintenance of personal protective equipment, including Respiratory Protective Equipment; safe waste disposal; and, practices for personal decontamination. The training environment must be designed in a manner to allow for engineering controls, such as on-tool water suppression or on-tool dust extraction, to be utilised.

High-mobility group box 1 promotes epithelial-to-mesenchymal transition in crystalline silica induced pulmonary inflammation and fibrosis

Silicosis is an inflammatory and fibrotic lung disease caused by prolonged inhalation of silica. The potential role of high-mobility group box-1 (HMGB-1) and its underlying mechanisms in silicosis remain unclear. In this study, intratracheal instillation of a silica suspension was used to establish silicosis in male C57BL/6 mice. To elucidate the effects of HMGB-1 on the pathogenesis of silicosis, we used HMGB-1 neutralizing antibody (anti-HMGB-1) and recombinant HMGB-1 (rmHMGB-1) to abrogate or increase the HMGB-1 levels, respectively. At days 7, 28, and 84, the accumulation of macrophages and neutrophils decreased by anti-HMGB-1 treatment. The expression levels of interleukin-6 and tumor necrosis factor-α in lung increased in response to silica exposure across three time points; anti-HMGB-1 could alleviate those expressions at day 28 and 84. In contrast, rmHMGB-1 aggravated this process. At days 28 and 84, the protein expression of fibronectin and col1a1 decreased in the silica + anti-HMGB-1 groups but increased in silica + rmHMGB-1 groups compared to mice with silica alone. Further study suggested that HMGB-1-mediated epithelial-mesenchymal transition participated in the development of silicosis. In conclusion, the findings demonstrate that HMGB-1 participates in the pathogenesis of silicosis and may represent a potential therapeutic target for the treatment of silicosis.

Performance Comparison of Four Portable FTIR Instruments for Direct-on-Filter Measurement of Respirable Crystalline Silica.

Exposure to dusts containing respirable crystalline silica is a recognized hazard affecting various occupational groups such as miners. Inhalation of respirable crystalline silica can lead to silicosis, which is a potentially fatal lung disease. Currently, miners' exposure to respirable crystalline silica is assessed by collecting filter samples that are sent for laboratory analysis. A more timely field-based silica monitoring method using direct-on-filter (DoF) analysis is being developed by researchers at the National Institute for Occupational Safety and Health (NIOSH) to provide mine operators with the option to evaluate miners' exposure at the mine. This field-based silica monitoring technique involves the use of portable Fourier transform infrared (FTIR) instruments. As a step in the development of this new analytical technique, four commercially available portable FTIR instruments were evaluated for their ability to provide reproducible measurements from filter samples containing respirable crystalline silica. Reported testing indicates that measurements varied within ±4.1% between instruments for filter samples that contained high-purity respirable crystalline silica. Measurements varied within ±3.0% between instruments for filter samples that contained varying mineral composition. Filter samples were repeatedly analyzed by the same instrument over short and extended periods of time, and mean coefficients of variation did not exceed ±1.6 and ±2.4%, respectively. Mixed model analysis revealed that there was no statistically significant (P < 0.05) change in average measurements made over an extended period of time for all instruments. Results suggest that each of the four FTIR instruments evaluated in this study were able to generate precise and reproducible DoF analysis results of respirable dust samples.

Intragastric administration of dahuang zhechong pill modulates TGF-β1/smad signaling pathway in murine model of experimental silicosis

ObjectivesSince DHZCP had significant inhibitory effects on liver and kidney fibrosis, we hypothesize that DHZCP could also inhibit pulmonary fibrosis. Therefore, the aim of this study is to examine the effect of DHZCP on silicosis, a type of pulmonary fibrosis caused by silica dust, and its underlying mechanism. MethodsPulmonary fibrosis was induced by inhalation of silica (SiO2) dust in mice which were then randomly divided into 5 groups: pulmonary fibrosis model group, high-dose DHZCP group, medium-dose DHZCP group, low-dose DHZCP group and Tetrandrine group. The normal control group mice were not exposed to SiO2 dust. After 28 days of continuous intragastric administration of DHZCP, the mice were sacrificed. The histopathology of lungs, the levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and hydroxyproline (HYP) in serum. Besides, the expression of transforming growth factor‑β1 (TGF-β1), α-smooth muscle actin (α-SMA), Smad2, Smad3 and Smad7 in lung tissue were examined. ResultsThe mice with silicosis was generated with an observed inflamed lung tissues and elevated inflammatory cytokines. DHZCP significantly reduced serum levels of TNF-α, IL-6, IL-1β and HYP in mice with lung fibrosis. DHZCP treatment remarkably downregulated mRNA and protein levels of TGF-β1, α-SMA, Smad2 and Smad3 in lung tissue, while increased the protein level of Smad7. ConclusionsThese results demonstrated that DHZCP could alleviate pulmonary fibrosis induced by SiO2. The anti-fibrotic effects of DHZCP are conferred by decreasing inflammation and pulmonary fibrosis, which may be related to the TGF-β1/Smad pathway.

Tanshinone IIA attenuates silica-induced pulmonary fibrosis via Nrf2-mediated inhibition of EMT and TGF-β1/Smad signaling

Silicosis is an occupational pulmonary fibrosis that is caused by inhalation of silica (SiO2), and there are no effective drugs to treat this disease. Tanshinone IIA (Tan IIA), a natural product, has been reported to possess antioxidant and anti-fibrotic properties in various diseases. The purpose of the current study was to examine Tan IIA's protective effects against silica-induced pulmonary fibrosis and to explore the underlying mechanisms. We found that in vivo treatment with Tan IIA significantly relieved silica-induced lung fibrosis in a silicosis rat model by histological and immunohistochemical analyses. Further, in vitro mechanistic investigations, mainly using western blot and immunofluorescence analyses, revealed that Tan IIA administration markedly inhibited the silica-induced epithelial-mesenchymal transition (EMT) and transforming growth factor-β1 (TGF-β1)/Smad signaling pathway and also reduced silica-induced oxidative stress and activated the nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway in A549 and human bronchial epithelial (HBE) cells. Furthermore, through transfection with siRNA, we demonstrate that Nrf2 activation partially mediates the suppression effects of Tan IIA on EMT and TGF-β1/Smad signaling pathway activation induced by silica exposure, thus mediating the anti-fibrotic effects of Tan IIA against silica-induced pulmonary fibrosis. In our study, Tan IIA has been identified as a possible anti-oxidative and anti-fibrotic drug for silicosis.

Crystalline Silica Impairs Efferocytosis Abilities of Human and Mouse Macrophages: Implication for Silica-Associated Systemic Sclerosis.

Inhalation of crystalline silica (SiO2) is a risk factor of systemic autoimmune diseases such as systemic sclerosis (SSc) and fibrotic pulmonary disorders such as silicosis. A defect of apoptotic cell clearance (i.e., efferocytosis, a key process in the resolution of inflammation) is reported in macrophages from patients with fibrotic or autoimmune diseases. However, the precise links between SiO2 exposure and efferocytosis impairment remain to be determined. Answering to this question may help to better link innate immunity and fibrosis. In this study, we first aim to determine whether SiO2 might alter efferocytosis capacities of human and mouse macrophages. We secondly explore possible mechanisms explaining efferocytosis impairment, with a specific focus on macrophage polarization and on the RhoA/ROCK pathway, a key regulator of cytoskeleton remodeling and phagocytosis. Human monocyte-derived macrophages (MDM) and C57BL/6J mice exposed to SiO2 and to CFSE-positive apoptotic Jurkat cells were analyzed by flow cytometry to determine their efferocytosis index (EI). The effects of ROCK inhibitors (Y27632 and Fasudil) on EI of SiO2-exposed MDM and MDM from SSc patients were evaluated in vitro. Our results demonstrated that SiO2 significantly decreased EI of human MDM in vitro and mouse alveolar macrophages in vivo. In human MDM, this SiO2-associated impairment of efferocytosis, required the expression of the membrane receptor SR-B1 and was associated with a decreased expression of M2 polarization markers (CD206, CD204, and CD163). F-actin staining, RhoA activation and impairment of efferocytosis, all induced by SiO2, were reversed by ROCK inhibitors. Moreover, the EI of MDM from SSc patients was similar to the EI of in vitro- SiO2-exposed MDM and Y27632 significantly increased SSc MDM efferocytosis capacities, suggesting a likewise activation of the RhoA/ROCK pathway in SSc. Altogether, our results demonstrate that SiO2 exposure may contribute to the impairment of efferocytosis capacities of mouse and human macrophages but also of MDM in SiO2-associated autoimmune diseases and fibrotic disorders such as SSc; in this context, the silica/RhoA/ROCK pathway may constitute a relevant therapeutic target.

Caplan's Syndrome with a twist.

Caplan’s syndrome is seen in patients with rheumatoid arthritis (RA) and chronic silica inhalation. We present a patient with RA who presented with multiple pulmonary nodules. Biopsy of the nodules revealed silica crystals under polarized light. He continued treatment for RA and his pulmonary nodules remained stable. However, he subsequently developed renal failure with nephrotic range proteinuria. We discuss silica and the associated autoimmunity in patients with chronic occupational exposure.BackgroundCaplan’s syndrome also known as rheumatoid pneumoconiosis is a disease entity that is seen in patients with rheumatoid arthritis (RA) exposed to chronic silica and inorganic dust [1,2]. Classically, they form peripheral well-defined pulmonary nodules with characteristic silica retained in the necrobiotic center. In addition, epidemiological data has shown some association with silica and autoimmunity [3]. We present a case of silica and asbestosis exposure in a patient with rheumatoid arthritis who developed rheumatoid pneumoconiosis and subsequent renal failure. We highlight this rare disease, progression as well as other associated complications.

The Protective Role of Tanshinone IIA in Silicosis Rat Model via TGF-β1/Smad Signaling Suppression, NOX4 Inhibition and Nrf2/ARE Signaling Activation.

PurposeSilicosis is an occupational disease caused by inhalation of silica and there are no effective drugs to treat this disease. Tanshinone IIA (Tan IIA), a traditional natural component, has been reported to possess anti-inflammatory, antioxidant, and anti-fibrotic properties. The current study’s purpose was to examine Tan IIA’s protective effects against silica-induced pulmonary fibrosis and to explore the underlying mechanisms.Methods48 male SD rats were randomly divided into four groups (n=12): i) Control group; ii) Silicosis group; iii) Tan IIA group; iv) Silicosis +Tan IIA group. Two days after modeling, the rats of Tan IIA group and Silicosis +Tan IIA group were given intraperitoneal administration 25 mg/kg/d Tan IIA for 40 days. Then, the four groups of rats were sacrificed and the lung inflammatory responses were measured by ELISA, lung damage and fibrosis were analyzed by hematoxylin and eosin (H&E) staining and Masson staining, the expression levels of collagen I, fibronectin and α-smooth muscle actin (α-SMA) were measured by immunohistochemistry. The markers of oxidative stress were measured by commercial kits, and the activity of the TGF-β1/Smad and NOX4, Nrf2/ARE signaling pathways were measured by RT-PCR and Western blotting.ResultsThe silica-induced pulmonary inflammtory responses, structural damage and fibrosis were significantly attenuated by Tan IIA treatment. In addition, treatment with Tan IIA decreased collagen I, fibronectin and α-SMA expression, and inhibited TGF-β1/Smad signaling in the lung tissue. The upregulated levels of oxidative stress markers in silicosis rats were also markedly restored following Tan IIA treatment. Furthermore, treatment with Tan IIA reduced NOX4 expression and enhanced activation of the Nrf2/ARE pathway in the lung tissue of silicosis rats.ConclusionThese findings suggest that Tan IIA may protect lung from silica damage via the suppression of TGF-β1/Smad signaling, inhibition of NOX4 expression and activation of the Nrf2/ARE pathway.

Inhibition of miR-155-5p Exerts Anti-Fibrotic Effects in Silicotic Mice by Regulating Meprin α

Silicosis is a fatal profession-related disease linked to long-term inhalation of silica. The present study aimed to determine whether meprin α, a master regulator of anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), is diminished by miR-155-5p in silicotic and control lung macrophages and fibroblasts upon activation. NR8383 macrophages, primary lung fibroblasts, and mouse embryonic fibroblasts were used to evaluate the expression and function of meprin α and miR-155-5p. In vitro meprin α manipulation was performed by recombinant mouse meprin α protein, actinonin (its inhibitor), and small interfering RNA knockdown. Macrophage and fibroblast activation was assessed by western blotting, real-time PCR, matrix deposition, and immunohistochemical staining. The roles of meprin α and miR-155-5p were also investigated in mice exposed to silica. We found that the meprin α level was stably repressed in silicotic rats. In vitro, silica decreased meprin α, and exogenous meprin α reduced activation of macrophages and fibroblasts induced by profibrotic factors. miR-155-5p negatively regulated Mep1a by binding to the 3′ untranslated region. Treatment with anti-miR-155-5p elevated meprin α, ameliorated macrophage and fibroblast activation, and attenuated lung fibrosis in mice induced by silica. The sustained repression of meprin α and beneficial effects of its rescue by inhibition of miR-155-5p during silicosis indicate that miR-155-5p/meprin α are two of the major regulators of silicosis.

Interleukin 1α and 1β gene variations are associated with tuberculosis in silica exposed subjects.

Silicosis is a fibrotic lung disease resulting from the inhalation of crystalline silica and can be classified as simple or complicated according to the International Labour Organization criteria. Furthermore, individuals exposed to crystalline silica also have a higher risk for the development of tuberculosis (Tb). The contribution of inflammatory cytokines to the risk of silicosis and Tb in different populations has previously been reported. Since genetic background might be related to susceptibility to silicosis and Tb, the study of polymorphisms within IL-1α, IL-1β, and tumor necrosis factor protein-coding genes may contribute to elucidating the genetic basis of these diseases. Single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction using restriction fragment length polymorphism or by Taqman methodology, in a sample of 102 silica-exposed patients from Brazil. No significant associations were observed between the SNPs studied and the severity of silicosis. However, significant associations were found between Tb and the C allele (odds ratio [OR] = 1.93, 95% confidence interval [CI], 1.01-3.73) and the CC genotype (OR = 2.34, 95% CI, 1.04-5.31) of IL1A -899C>T. The IL1B +3954C>T polymorphism also showed an association with Tb (T allele dominant model OR = 2.38, 95% CI, 1.04-5.41). These preliminary results demonstrate that the IL1A and IL1B gene variations may contribute to some extent to susceptibility to Tb, but not silicosis. However, additional studies are still needed to confirm these results.

EPIDEMIOLOGICAL STUDY OF SILICOSIS WITH BILATERAL SPONTANEOUS PNEUMOTHORAX IN RAJASTHAN

Background: Silicosis is reported to be an occupational lung disease, which is caused by the inhalation of silica dust. Workers in occupations related to silica dust exposure are characterized by increased foci of fibrogenesis which result in radiological and pathological findings in the lungs. In most circumstances silicosis only develops subsequent to substantial occupational exposures.&#x0D; Material &amp; Methods: The present prospective study was conducted at department of respiratory medicine of our tertiary care hospital. The study was an observational study conducted during a period of one year. The study done at 95% confidence interval at 10% of maximum allowable error. All patients who were diagnosed with silicosis were enrolled into the study.&#x0D; Results: In the present study, all patient had cough at presentation out which 7 (70%) patients had dry cough and 3 patients with productive coughs, four patients experienced loss of appetite. Eight (80%) patients had a history of smoking. Chest X-rays of all patients revealed bilateral, widespread, reticulonodular, and nodular appearances. Six patients had work on crusher machine and four patients as manual stone cutter. Pneumothorax was located bilaterally in all cases.&#x0D; Conclusion: We concluded from the present study that inhalation of quartz dust or silica dusts was commonly associated with adverse health effects and it can cause serious morbidity like secondary spontaneous pneumothorax and mortalities.&#x0D; Keywords: Silicosis, occupational lung disease, secondary spontaneous pneumothorax.

Pathological Study on Epithelial-Mesenchymal Transition in Silicotic Lung Lesions in Rat

Silicosis, caused by the inhalation of crystalline silicon dioxide or silica, is one of the most severe occupational diseases. Persistent inflammation and progressive massive pulmonary fibrosis are the most common histological changes caused by silicosis. Association of epithelial-mesenchymal transition (EMT) of hyperplastic type II epithelial cells with the fibrotic events of pulmonary fibrosis has been suggested in in vitro silica-exposed cultured cell models, patients with idiopathic pulmonary fibrosis, and bleomycin-induced experimental models. Histological features of EMT, however, are not fully described in silicotic lungs in in vivo. The purpose of this study was to demonstrate EMT of hyperplastic type II epithelial cells in the developmental process of progressive massive pulmonary fibrosis in the lungs of rats exposed to silica. F344 female rats were intratracheally instilled with 20 mg of crystalline silica (Min-U-Sil-5), followed by sacrifice at 1, 3, 6, and 12 months after instillation. Fibrosis, characterized by the formation of silicotic nodules, progressive massive fibrosis, and diffuse interstitial fibrosis, was observed in the lungs of the treated rats; the effects of fibrosis intensified in a time-dependent manner. Hyperplasia of the type II epithelial cells, observed in the massive fibrotic lesions, dominated in the lungs of rats at 6 and 12 months after the treatment. Immunohistochemistry of the serial sections of the lung tissues demonstrated positive labeling for cytokeratin, vimentin, and α-smooth muscle actin in spindle cells close to the foci of hyperplasia of type II epithelial cells. Spindle cells, which exhibited features of both epithelial cells and fibroblasts, were also demonstrated with bundles of collagen fibers in the fibrotic lesions, using electron microscopy. Increased expression of TGF-β was shown by Western blotting and immunohistochemistry in the lungs of the treated rats. These findings suggested that enhanced TGF-β expression and EMT of hyperplastic type II epithelial cells are involved in the development process of progressive massive pulmonary fibrosis during silicosis.

Silicosis in Artificial Quartz Conglomerate Workers

IntroductionSilicosis is a chronic progressive disease caused by inhalation of crystalline silica. Most cases develop in underground mine workers and in subjects involved in the extraction of natural stone (slate and granite). In view of the progressive emergence of new cases of silicosis in artificial quartz conglomerate workers, we performed a study to analyze the characteristics of silicosis produced by this new agent in Spain. MethodsThe study consisted of a series of 96 cases of silicosis diagnosed according to international criteria during the period 2010–2017. We analyzed clinical, radiological, pathological and functional characteristics. ResultsMean age of participants was 45 years; 55% had simple silicosis and 45% had complicated silicosis. Ten patients were diagnosed with accelerated silicosis, with a mean age of 33 years. Mean time of exposure to conglomerates was 15 years, and 77% had not used appropriate protection measures. Half of the patients were asymptomatic and presented different classic forms on chest X-ray and chest high-resolution computed tomography, along with ground-glass images. No lung function changes were recorded. ConclusionsSilicosis in artificial quartz conglomerate workers occurs in a young, actively employed population, a considerable percentage of whom present an accelerated form. They have few symptoms and no functional limitations. Protection measures are scarce. It is important to characterize these features to provide early diagnosis and implement the necessary preventive measures.

Inhibition of miR-155-5p Exerts Anti-Fibrotic Effects in Silicotic Rats by Regulating Meprin α

Silicosis is a fatal profession-related disease linked to long term inhalation of silica. The present study aimed to determine whether meprin α, a master regulator of anti-fibrotic peptide N-acetyl-serylaspartyl-lysyl-proline (Ac-SDKP), is diminished by miR-155-5p in silicosis and control lung macrophages and fibroblasts upon activation. RAW 264.7 macrophages, primary lung fibroblasts, and mouse embryonic fibroblasts were used to evaluate the expression and function of meprin α and miR-155-5p. In vitro meprin α manipulation was performed by recombinant mouse meprin α protein, actinonin (its inhibitor), and small interfering RNA knockdown. Macrophage and fibroblast activation was assessed by western blotting, real-time PCR, matrix deposition, immunohistochemistry, and immunofluorescence staining. The roles of meprin α and miR-155-5p were also investigated in mice exposed to silica. We found that the meprin α level was stably repressed in silicotic rats.In vitro, silica decreased meprin α, and exogenous meprin α reduced activation of macrophages and fibroblasts induced by profibrotic factors. MiR-155-5p negatively regulated Mep1a by binding to the 3′ untranslated region. Treatment with anti-miR-155-5p elevated meprin α, ameliorated macrophage and fibroblast activation, and attenuated lung fibrosis in mice induced by silica. The sustained repression of meprin α and beneficial effects of its rescue by inhibition of miR-155-5p during silicosis indicate that miR-155-5p/meprin α are major regulators of silicosis. Funding Statement: This work was supported by the National Natural Science Foundation of China (No. 81472953), the Natural Science Foundation of Hebei Province (No. H20162091705), Science and Technology Research Project of Hebei Province universities (No. ZD2019077), and the Preeminence Youth Foundation of North China University of Science and Technology (JP201513). Declaration of Interests: The authors declare they have no competing interests. Ethics Approval Statement: All experimental and surgical procedures were approved (2013-038 and 2017-025) by the Ethics Committee for Animal Experimentation of North China University of Science and Technology, which complies with the US National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Prevention of crystalline silica-induced inflammation by the anti-malarial hydroxychloroquine

Objectives: Inhalation of crystalline silica (cSiO2) remains a significant occupational hazard and may lead to the development of silicosis. When cSiO2 particles are phagocytized by alveolar macrophages, they cause disruption of the lysosomal membrane which results in cell death. There are currently no pharmaceutical treatments directed at this mechanism of disease; however, many existing pharmaceuticals, such as hydroxychloroquine (HCQ), become sequestered in the lysosome through an ion-trapping mechanism. The objective of this research was to determine whether HCQ can prevent cSiO2-induced toxicity by blocking LMP in alveolar macrophages.Materials and methods: This study assessed the ability of in vitro treatment with HCQ to block toxicity and lysosomal membrane permeability in cSiO2-exposed mouse bone-marrow derived macrophages. Additionally, C57Bl/6 mice were treated with HCQ by oral gavage before cSiO2 exposure, and the ability of HCQ to prevent lung injury and inflammation was assessed.Results: In vitro studies demonstrated that HCQ attenuated activation of the NLRP3 inflammasome and blocked LMP. Mice treated with HCQ in vivo showed a modest trend towards decreased cSiO2-induced toxicity. Ex vivo culture of alveolar macrophages collected from cSiO2-treated mice showed significantly less NLRP3 inflammasome activation after in vivo exposure to HCQ.Conclusions: Our findings suggest that hydroxychloroquine blocks LMP and can significantly decrease cSiO2-induced toxicity in vitro. HCQ may be a promising treatment for prevention of cSiO2-induced lung damage.

Silicosis en trabajadores con conglomerados artificiales de cuarzo

IntroductionSilicosis is a chronic progressive disease caused by inhalation of crystalline silica. Most cases develop in underground mine workers and in subjects involved in the extraction of natural stone (slate and granite). In view of the progressive emergence of new cases of silicosis in artificial quartz conglomerate workers, we performed a study to analyze the characteristics of silicosis produced by this new agent in Spain. MethodsThe study consisted of a series of 96 cases of silicosis diagnosed according to international criteria during the period 2010-2017. We analyzed clinical, radiological, pathological and functional characteristics. ResultsMean age of participants was 45 years; 55% had simple silicosis and 45% had complicated silicosis. Ten patients were diagnosed with accelerated silicosis, with a mean age of 33 years. Mean time of exposure to conglomerates was 15 years, and 77% had not used appropriate protection measures. Half of the patients were asymptomatic and presented different classic forms on chest X-ray and chest high-resolution computed tomography, along with ground-glass images. No lung function changes were recorded. ConclusionsSilicosis in artificial quartz conglomerate workers occurs in a young, actively employed population, a considerable percentage of whom present an accelerated form. They have few symptoms and no functional limitations. Protection measures are scarce. It is important to characterize these features to provide early diagnosis and implement the necessary preventive measures.

Artificial Stone Associated Silicosis: A Systematic Review.

Silicosis is a progressive fibrotic lung disease that is caused by the inhalation of respirable crystalline silica. Due to its high silica content, artificial stone (AS) can become a possible source of hazardous dust exposure for workers that are employed in the manufacturing, finishing, and installing of AS countertops. Therefore, the aim of this review was to verify the association between AS derived silica exposure and silicosis development, and also then define the pathological characteristics of the disease in relation to specific work practices and preventive and protective measures that were adopted in the workplace. A systematic review of articles available on Pubmed, Scopus, and Isi Web of Knowledge databases was performed. Although the characteristics of AS-associated silicosis were comparable to those that were reported for the disease in traditional silica exposure settings, some critical issues emerged concerning the general lack of suitable strategies for assessing/managing silica risks in these innovative occupational fields. Further research that is designed to assess the hazardous properties of AS dusts, levels of exposure in workplaces, and the effectiveness of protective equipment appears to be needed to increase awareness concerning AS risks and induce employers, employees, and all factory figures that are engaged in prevention to take action to define/adopt proper measures to protect the health of exposed workers.

Initiation of Pulmonary Fibrosis after Silica Inhalation in Rats is linked with Dysfunctional Shelterin Complex and DNA Damage Response

Occupational exposure to silica has been observed to cause pulmonary fibrosis and lung cancer through complex mechanisms. Telomeres, the nucleoprotein structures with repetitive (TTAGGG) sequences at the end of chromosomes, are a molecular “clock of life”, and alterations are associated with chronic disease. The shelterin complex (POT1, TRF1, TRF2, Tin2, Rap1, and POT1 and TPP1) plays an important role in maintaining telomere length and integrity, and any alteration in telomeres may activate DNA damage response (DDR) machinery resulting in telomere attrition. The goal of this study was to assess the effect of silica exposure on the regulation of the shelterin complex in an animal model. Male Fisher 344 rats were exposed by inhalation to Min-U-Sil 5 silica for 3, 6, or 12 wk at a concentration of 15 mg/m3 for 6 hr/d for 5 consecutive d/wk. Expression of shelterin complex genes was assessed in the lungs at 16 hr after the end of each exposure. Also, the relationship between increased DNA damage protein (γH2AX) and expression of silica-induced fibrotic marker, αSMA, was evaluated. Our findings reveal new information about the dysregulation of shelterin complex after silica inhalation in rats, and how this pathway may lead to the initiation of silica-induced pulmonary fibrosis.